Abstract
SUMMARYRecent studies indicated that sortilin-related receptor 1 (SORL1) is a risk gene for late-onset Alzheimer's disease (AD), although its role in the aetiology and/or progression of this disorder is not fully understood. Here, we report the finding of a non-coding (nc) RNA (hereafter referred to as 51A) that maps in antisense configuration to intron 1 of the SORL1 gene. 51A expression drives a splicing shift of SORL1 from the synthesis of the canonical long protein variant A to an alternatively spliced protein form. This process, resulting in a decreased synthesis of SORL1 variant A, is associated with impaired processing of amyloid precursor protein (APP), leading to increased Aβ formation. Interestingly, we found that 51A is expressed in human brains, being frequently upregulated in cerebral cortices from individuals with Alzheimer's disease. Altogether, these findings document a novel ncRNA-dependent regulatory pathway that might have relevant implications in neurodegeneration.
Highlights
Sortilin-related receptor 1 (SORL1; known as sorting proteinrelated receptor 1 and LR11) is a 250-kDa type-1 membrane protein of unknown function that is expressed in neurons of the central and peripheral nervous system (Jacobsen et al, 1996; Yamazaki et al, 1996; Hermans-Borgmeyer et al, 1998; Motoi et al, 1999)
The authors describe a new ncRNA that maps in an antisense orientation in intron 1 of the sortilin-related receptor 1 (SORL1) gene and whose synthesis promotes the expression of alternatively spliced SORL1 variants
Mask canonical splicing sites, leading to alternative splicing events. By addressing such a hypothesis, in this work we demonstrate that: (i) 51A is a newly identified ncRNA whose synthesis promotes the expression of SORL1 alternatively spliced protein variants to the detriment of the canonical SORL1 splice variant A; (ii) this event triggers an altered processing of amyloid precursor protein (APP) that leads to its impaired internalisation; (iii) this process leads to increased amyloid secretion; and (iv) 51A is upregulated in post-mortem cerebral cortices from individuals with Alzheimer’s disease (AD)
Summary
Sortilin-related receptor 1 (SORL1; known as sorting proteinrelated receptor 1 and LR11) is a 250-kDa type-1 membrane protein of unknown function that is expressed in neurons of the central and peripheral nervous system (Jacobsen et al, 1996; Yamazaki et al, 1996; Hermans-Borgmeyer et al, 1998; Motoi et al, 1999). The initial processing of amyloid precursor protein (APP) by α- and β-secretases is intimately associated with post-Golgi compartments and requires efficient transition of the precursor through these organelles (Haass et al, 1993; Yamazaki et al, 1995). In this context, SORL1 interacts with APP and affects its trafficking and proteolytic processing in the brain, acting as a sorting receptor for APP holoprotein. The absence or downregulation of SORL1 expression shifts APP holoprotein from the retromer recycling pathway to the βsecretase cleavage pathway, increasing secreted APP (sAPPβ) production and, subsequently, Aβ formation (Peraus et al, 1997; Khvotchev and Südhof, 2004)
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